title: Human β-defensin-2 enhances IFN-γ and IL-10 production and suppresses IL-17 production in T cells.
abstract: Psoriasis is an inflammatory dermatosis with enhanced expression of hBD-2 in keratinocytes and infiltration of cytokine-producing T cells, which in turn, up- or down-regulate hBD-2 expression. We determined the serum levels of hBD-2 and cytokines in psoriasis patients and analyzed the effects of hBD-2 on cytokine production in human peripheral blood T cells. Serum hBD-2 levels in patients were higher than those in controls and correlated with PASI, serum IFN-γ, and IL-10 levels and correlated inversely with serum IL-17 levels. IFN-γ, IL-17, IL-22, TNF-α, IL-1β, and IL-6 enhanced, and IL-10, IL-4, and IL-13 suppressed hBD-2 secretion from keratinocytes. hBD-2 enhanced secretion and mRNA levels of IFN-γ, TNF-α, IL-10, IL-1β, IL-6, and IL-22 and reduced those of IL-17 in CD3/28-stimulated T cells. These effects of hBD-2 were counteracted by PTX. hBD-2 induced phosphorylation of JNK, ERK, and Akt in T cells. Inhibitors of these signals attenuated hBD-2-induced production of IFN-γ, TNF-α, IL-10, IL-1β, IL-6, and IL-22. hBD-2 suppressed phosphorylation of STAT3 and enhanced expression of SOCS3 in CD3/28-stimulated T cells. siRNA against SOCS3 reversed hBD-2-induced suppression of IL-17 production and STAT3 phosphorylation. JNK and MEK inhibitors suppressed hBD-2-induced expression of SOCS3. In conclusion, hBD-2 may bind PTX-sensitive GPCR(s) on T cells and act as a stimulator by enhancing IFN-γ, TNF-α, IL-1β, IL-6, and IL-22 production via JNK, MEK/ERK, and PI3K/Akt and as a regulator by suppressing IL-17 production via SOCS3 or by stimulating IL-10 production.
authors.affiliation: Department of Dermatology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-Ku, Tokyo 173-8605, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamata
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Tada
authors.forename: Takeko
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D052816:Foreskin / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells; D023083:beta-Defensins / Q000494:pharmacology*; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D016753:Interleukin-10; D020381:Interleukin-17; D007378:Interleukins; D037342:Pertussis Toxin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D023083:beta-Defensins; D000097043:Interleukin-22; C106641:DEFB4A protein, human; C106644:SOCS3 protein, human; C494086:STAT3 protein, human